Long-term survival based on pathologic response to neoadjuvant therapy in esophageal cancer.

BACKGROUND: Neoadjuvant treatment is standard for locally advanced esophageal cancer. However, whether the addition of radiation to neoadjuvant regimen improves survival remains unclear. The aim of this study was to compare survival in locally advanced esophageal cancer treated with neoadjuvant chemotherapy versus chemoradiation. MATERIALS AND METHODS: A prospectively maintained database of esophagectomies (1999-2012) was analyzed. We identified 297 patients with locally advanced esophageal cancer that underwent either neoadjuvant chemotherapy (n = 231) or chemoradiation (n = 66) followed by esophagectomy. Pretreatment and pathologic staging were compared to assess response. Overall survival was recorded. RESULTS: Most patients in the chemotherapy and chemoradiation groups had pretreatment stage III disease (66.7% versus 65.2%; P = 0.44). Median follow-up was 79.3 and 64.9 mo for chemotherapy and chemoradiation cohorts, respectively. Complete response rate was higher in chemoradiation than chemotherapy groups (30.3% versus 13.8%; P < 0.001). Overall survival was similar between complete responders in both groups (median not reached versus 121.1 mo; chemotherapy versus chemoradiation). However, partial responders in the chemotherapy cohort had improved median survival (147.2 mo) versus those in the chemoradiation cohort (83.7 mo, P < 0.03). Within the chemotherapy-only group, partial responders had improved survival compared with nonresponders (P = 0.041); however, there was no difference in survival between partial and complete responders (P = 0.36). CONCLUSIONS: In patients undergoing esophagectomy for locally advanced esophageal cancer, neoadjuvant chemotherapy was associated with an equivalent overall survival, when compared with neoadjuvant chemoradiotherapy. Adding neoadjuvant radiation may enhance complete response rates but does not appear to be associated with improved survival.

Arsenic Attenuates GLI Signaling, Increasing or Decreasing its Transcriptional Program in a Context-Dependent Manner.

The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic's biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic-induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.

Depth of injury caused by liquid nitrogen cryospray: study of human patients undergoing planned esophagectomy.

BACKGROUND: Cryotherapy using liquid nitrogen delivered endoscopically has been used for mucosal ablation of esophageal neoplasia. There are no data for the human esophagus on the depth of injury and effects of this technique. AIM: Prospective study to examine the effect of treatment and depth of injury to the human esophagus of liquid nitrogen spray cryotherapy for subjects with esophageal neoplasia before planned esophagectomy. METHODS: Liquid nitrogen spray cryoablation was performed seven days before scheduled esophagectomy for seven males with esophageal carcinoma. Subjects were assigned to either treatment of four cycles of 10 s each (group 1) or two cycles of 20 s each (group 2) applied to a 2-cm segment of healthy esophagus above the tumor area. Main outcomes measured were: mean depth of injury (mm); surface displaying mucosal ablation, and adverse events. RESULTS: Mucosal destruction was similar for both groups (group 1, 95%; group 2, 93%; p = NS). Deeper injury was observed for group 2; mean depth was 5.4 mm compared with 4.0 mm for group 1. Cryonecrosis reached the submucosa for 60% (12/20) of subjects in group 1 versus 93% (14/15) of subjects in group 2 (p = 0.04, two-tailed Fisher's exact test). No serious adverse events occurred. No perforation was seen in the resected esophagus. CONCLUSION: Mucosal ablation with liquid nitrogen spray cryotherapy was highly effective in inducing mucosal necrosis; the doses assessed had similar effects. Ablation reached the submucosa more often with longer spray time despite fewer treatment cycles.

Influence of treatment modality in outcomes for different stages of resectable esophageal adenocarcinomas.

BACKGROUND: There is no consensus on the most effective modality for the treatment of resectable esophageal adenocarcinomas (EAC). We theorized that treatment modality may influence survival differently depending on the stage of disease. METHODS: A single-institution, retrospective examination of resectable EAC between 2000 and 2008 was performed. Resectable EAC were stratified into early disease (stage 2a or less) and late disease (stage 2b or more) based on pretreatment endoscopic ultrasound (EUS). Patients with T4, >N2, and/or distant disease were excluded. RESULTS: A total of 156 patients were included in this study. Most patients were white (97 %), male (83 %), and over 60 years of age (51 %). Patients with early disease on pretreatment EUS exhibited improved overall survival compared to patients with late disease (P < 0.001). Irrespective of treatment modality, there were no significant differences in overall 5-year survival for patients with early or late disease. Early and late disease patients whose disease responded to neoadjuvant chemotherapy (NAC) had significantly improved overall survival compared to nonresponsive disease (P < 0.05). The only negative independent predictors of overall 5-year survival were late stage disease on pretreatment EUS (hazard ratio 2.402, 95 % confidence interval 1.24-4.67, P = 0.01) and late stage disease on final pathological stage (hazard ratio 2.29, 95 % confidence interval 1.22-4.31, P = 0.01). CONCLUSIONS: Our data lack statistical power but reveal no difference in survival with the addition of neoadjuvant therapies to surgery for early or late resectable EAC. However, patients with disease that responded to NAC had improved outcomes at 5 years for both groups. Therefore, the prognosis for patients undergoing NAC may be optimized by immediate surgical resection if neoadjuvant therapies do not result in a dramatic clinical response.

Case report: Diagnosis of NUT carcinoma of hepatic origin by next-generation sequencing.

NUT carcinoma is a rare subcategory of squamous cell carcinoma. The latter is primarily characterized by the fusion of the coding sequence NUTM1 on chromosome 15q14 with BRD4 or BRD3, both of which are acetyl-histone binding bromodomains. This tumor is often misdiagnosed due to its rarity and its histological similarity with other squamous cell carcinomas. It typically presents as a poorly differentiated squamous cell carcinoma in the head, neck, and mediastinal region, and has no distinct clinical characteristics that set it apart from other malignancies. Although uncommon, other NUT carcinomas have been reported in the literature outside of the midline region. Through next-generation sequencing, we were able to correctly diagnose our patient with the first-documented case of NUT carcinoma of hepatic-only origin.

Does neoadjuvant chemotherapy improve outcomes for patients with gastric cancer?

BACKGROUND: The role of neoadjuvant and adjuvant therapy for gastric cancer remains undefined. We compared the outcomes for patients treated with surgery alone or with the addition of adjuvant or neaodjuvant treatment. METHODS: A single-institution, retrospective evaluation of a prospective database of gastric cancer patients treated from 2000 to 2008 was performed. RESULTS: Overall, 173 patients with gastric cancer underwent surgical extirpation. Of the 173 patients, 43% had early-stage disease (less than stage 2) and 57% had late-stage disease (stage 2 or greater; American Joint Committee on Cancer, 2010). The median survival from the date of diagnosis for those treated with neoadjuvant chemotherapy (NAC) (n = 35), adjuvant chemotherapy (n = 21), adjuvant chemoradiotherapy (n = 18), both NAC and adjuvant chemotherapy (n = 11), or surgery alone (n = 88) was 26.3, 17.3, greater than 60, greater than 60, and 50.3 months, respectively. The addition of NAC to surgery was detrimental to survival in those with early-stage disease (P = 0.002) and did not improve survival in those with late-stage disease (P = 0.687). For those with late-stage disease, surgery with adjuvant chemoradiotherapy exhibited the best overall survival compared with surgery alone (P = 0.021) or surgery with adjuvant chemotherapy (P = 0.01). Patients treated with NAC had a greater rate of R0 resection compared with surgery alone (P = 0.049). CONCLUSIONS: NAC for patients with gastric cancer does not significantly improve the overall outcomes for those with late-stage disease and could be detrimental to survival for those with early-stage disease. However, treatment with NAC resulted in an improved rate of R0 resection.

Pancreatic cancer presenting as bowel obstruction and role of next generation sequencing: A case report.

INTRODUCTION AND IMPORTANCE: Pancreatic adenocarcinoma is one of the leading causes of death. Presentation with colonic metastases is far less frequently reported in the literature and may be misdiagnosed as colonic adenocarcinoma. We report the case of a female patient with metastatic pancreatic adenocarcinoma that presented with a sigmoid obstruction. CASE PRESENTATION: A 66-year-old female presented with constipation and abdominal pain. She was found to have an obstructing sigmoid colon lesion, multiple metastatic lesions in the liver, and a pancreatic tail lesion. She underwent left hemicolectomy and ostomy placement. The gross pathology of the colon and needle biopsy of the liver was consistent of pancreatobiliary origin. Genomic screening performed, patient found to be KRAS G12R mutated. She was given one cycle of chemotherapy, thereafter was referred to hospice care. CLINICAL DISCUSSION: Primary metastatic pancreatic cancer is now the 2nd most diagnosed cancer in the United States after lung cancer. The prognosis for the malignancy is poor, patients are usually diagnosed late at the time that the tumor has metastasized to other organs. Colonic metastasis is a rarely seen and far less frequently reported in the literature. Next-generation-sequencing was performed at baseline to further characterize her tumor for any actionable mutations. CONCLUSION: Pancreatic adenocarcinoma is an aggressive malignancy with a poor prognosis. Next-generation-sequencing may offer targeted therapy if an actionable mutation is present such as our patient's, however due to late diagnosis, rapid clinical deterioration, and next-generation sequencing delay we were unable to alter the patient's outcome.

A phase II study of neoadjuvant and adjuvant chemotherapy with 5-fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel in the treatment of previously untreated advanced esophageal adenocarcinoma.

OBJECTIVE: A complete pathologic response to neoadjuvant chemotherapy, without the use of radiation, has infrequently been reported in operable chemo-naïve stage III esophageal adenocarcinoma patients. METHODS: Twenty-nine eligible patients were enrolled in the study. Neoadjuvant therapy consisted of 5-fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel and was administered in two 4-week cycles. Following therapy, patients underwent surgical resection. Those patients having residual disease were offered adjuvant chemotherapy. Patients having a complete pathologic response were not offered any further chemotherapy. RESULTS: Twenty-four out of 29 patients finished neoadjuvant therapy and underwent curative esophagectomy. Two patients were declared inoperable after treatment, and three patients died prior to surgery. The median follow-up on all patients was 20.2 months. Median progression-free survival and median overall survival were 13.6 and 21.4 months, respectively. Clinical response to neoadjuvant chemotherapy was seen in 21 out of 29 patients (72.4%). Complete pathologic response with neoadjuvant chemotherapy was seen in 4 out of 24 patients (16.7%). Those four patients have been alive and progression-free for 20-37 months. Grade 3-4 toxicities occurred in 16 of the 29 patients during neoadjuvant therapy. Grade 3-4 toxicities were seen in 6 out of 14 patients during adjuvant therapy. (18)F-fluorodeoxyglucose-positron emission tomography standardized uptake values of ≥8 correlated with better progression-free survival. CONCLUSION: 5-Fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel regimen is active in patients with esophageal adenocarcinoma. Toxicity profiles are manageable. Neoadjuvant chemotherapy allowed achievement of complete pathologic response without radiation. (18)F-fluorodeoxyglucose-positron emission tomography standardized uptake values might be prognostic.

Cobimetinib Plus Gemcitabine: An Active Combination in KRAS G12R-Mutated Pancreatic Ductal Adenocarcinoma Patients in Previously Treated and Failed Multiple Chemotherapies.

Purpose: The KRAS proto-oncogene is involved in the RAS/MAPK pathway. KRAS is present in the wild type or mutated forms. The oncogene KRAS is frequently mutated in various cancers. At the time that amino acid glycine is mutated, KRAS protein acquires oncogenic properties that result in the tumor cell growth, proliferation, and cancer progression. There has been limited understanding of the different mutations at codon 12. The consequences of such mutations is not fully understood. Various G12X mutations in pancreatic cancer patients have been examined, with the most common mutations being G12D (40%), G12V (30%), and G12R (15-20%). Now we are understanding that G12X mutations in the KRAS are not all equal. Methods: In a single-arm exploratory study, we accrued 13 KRAS-G12X-mutated pancreatic patients (KRAS G12D, G12V, and G12R). They were divided into two groups: group 1 consisted of seven patients with G12D and G12V and group 2 included six patients with the KRAS G12R mutation. All patients were treated with the combination of gemcitabine at 1250 mg/m2 intravenous weekly for 3 weeks and oral cobimetinib 20 mg b.i.d. for 3 weeks. This was followed by a week of rest before the initiation of the next cycle. Results: In the first cohort, seven patients were on treatment, all of whom progressed and died within the 2 months of the study. In the second cohort, one of six patients achieved partial response, and five achieved stable disease. Median progression-free survival was 6 months (9% confidence interval 3.0-9.3 months) and overall survival has been reached at 8 months. Common adverse reactions included rash, fatigue, nausea, and vomiting (grades 2 and 3). Cancer antigen CA19-9 decreased by >50% in all group 2 patients. Conclusion: Our pancreatic cancer patients were heavily pretreated (all had received FOLFIRINOX and gemcitabine/nab-paclitaxel) before the entry into our trial. Upon entry into our trial, all patients were treated with the combination of gemcitabine and oral cobimetinib. Therefore, this constituted the second exposure of the patients to gemcitabine. This study illustrates a new discovery, which can potentially target 15-20% of pancreatic cancer patients and allow for a significant improvement in their prognosis. We will be conducting randomized phase II trials to substantiate our findings.

Potential benefit of treatment with MEK inhibitors and chemotherapy in BRAF-mutated KRAS wild-type pancreatic ductal adenocarcinoma patients: a case report.

This is the first case report of a 60-yr-old female who underwent therapy for metastatic pancreatic cancer with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Upon the progression of her disease, she was switched to gemcitabine and nab-paclitaxel. Per genomic sequencing, her tumor was found to be a KRAS wild-type and BRAF V600E mutation, which then warranted treatment with the MEK1 and MEK2 inhibitor, cobimetinib. The patient has achieved a complete response (CR) to a combination of gemcitabine, nab-paclitaxel, and cobimetinib. It has been 16 mo since the start of the treatment, and the patient continues to demonstrate a complete durable response both serologically and radiologically.

Neoadjuvant, surgery and adjuvant chemotherapy without radiation for esophageal cancer.

BACKGROUND: A phase II trial to evaluate neoadjuvant (NAD), surgery and adjuvant (AD) combination chemotherapy without radiation therapy (RT) for patients with esophageal adenocarcinoma staged with endoscopic ultrasound and CT as T3N1 was carried out. METHODS: Thirty-three eligible patients were enrolled. NAD therapy was administered in two 49-day cycles and included cisplatin, floxuridine, paclitaxel and leucovorin. Esophageal resection was performed followed by AD therapy. RESULTS: Thirty-three patients initiated NAD therapy; 10 experienced grade 3 and 4 toxicities, which included leucopenia, fatigue, nausea, diarrhea and stomatitis. Additionally, 16 patients experienced grade 1 and 2 hematologic and non-hematologic toxicities. Fifteen patients were down-staged, of whom five were T2, seven were T1, and three had nodal disease with no evidence of residual cancer in the esophageal bed. Fifteen patients remained T3, and two showed progressive disease. Thirty-two patients proceeded to surgery and 30 were resected. Although all resected patients were eligible for AD therapy, 15 did not receive it either because of patient refusal or surgeon recommendation. Fifteen patients received AD therapy: nine who had remained T3 and six who had down-staged. Three patients experienced grade 3 and 4 toxicities similar to those in NAD therapy. Six patients had grade 1 and 2 toxicities. Kaplan-Meier estimates of overall survival at 1, 3 and 5 years were 73% (95% CI: 58-88%), 52% (95% CI: 34-69%) and 29% (95% CI: 13-45%), respectively. Median survival was 42 months. CONCLUSION: Deletion of RT may safely allow for more aggressive chemotherapy and increase chances of survival. The results need to be confirmed in a randomized phase II or larger phase III trial.

Treatment of advanced colorectal cancer in a patient with cardiotoxic reactions to 5-fluorouracil and capecitabine using suboptimal doses.

A 32-year-old female with stage IV colorectal cancer and metastasis to the liver experienced cardiotoxic reactions after treatment with 5-fluorouracil and its oral prodrug capecitabine even at two-thirds the recommended dose. After careful considerations, the decision was made to attempt capecitabine retrial at a further suboptimal dose with combination chemotherapy where she no longer experienced cardiac events. As a result, the liver tumour shrank and rectal mass stabilised, tumour markers dropped and she underwent surgical resection of both masses. Later there was local recurrence of disease near the previous liver tumour, so the suboptimal capecitabine therapy was restarted without complaint. The patient became a candidate for a NanoKnife procedure, offering a potentially curative therapy. This case report summarises a novel treatment strategy for those patients with advanced colorectal cancer who experience cardiotoxic reactions to fluoropyrimidines, the active agent of gold standard treatment.

A phase II trial of FUdR in patients with advanced pancreatic cancer.

PURPOSE: This phase II study was conducted to assess the efficacy of fluorodeoxyuridine (FUdR) in patients with metastatic, advanced pancreatic cancer who had no previous chemotherapy. PATIENTS AND METHODS: Twenty patients were enrolled in this single institution trial. The primary endpoint of this study was the assessment of overall survivorship. The secondary endpoints were to estimate the time to tumor progression and the assessment of toxicity in this cohort of patients. Treatment consisted of FUdR 150 mg/kg dissolved in 500 cc normal saline intravenous infusion over 24 h. Eight weeks of treatment constituted one course of chemotherapy. Tumor measurements were conducted at 8-weekly intervals. RESULTS: Four patients achieved partial response and 16 patients had stable disease. Median survival of patients treated with FUdR was 11.6 months with a range of 3-16 months. Median progression-free survival was 6 months. Overall, chemotherapy was well tolerated with low incidence of grade 3 or 4 toxicity. CONCLUSIONS: Systemic chemotherapy with high dose FUdR administered on a weekly schedule has led to encouraging survival outcomes and improved quality of life as compared to previous phase II single agent chemotherapeutic trials.

Effects of oxaliplatin and CPT-11 on cytotoxicity and nucleic acid incorporation of the fluoropyrimidines.

PURPOSE: The addition of oxaliplatin or CPT-11 to 5-FU has become common practice in the treatment of colorectal cancer. It is not known, however, which fluoropyrimidine drug (5-FU, FUdR, or FUR) will produce superior cytotoxicity when combined with either oxaliplatin or CPT-11. The purpose of the study was to determine the effects of oxaliplatin and CPT-11 on cytotoxicity and nucleic acid incorporation of all three fluoropyrimidines. METHODS: HT-29 cells were exposed for 2 h to IC(10), IC(30), and IC(70) of oxaliplatin and CPT-11. Subsequently, cells were exposed for 24 h to IC(10), IC(30), and IC(70) of 5-FU, FUdR, and FUR. Cytotoxicity was measured by the MTT assay. Nucleic acid incorporation of [(3)H]fluoropyrimidine was then compared in the presence and absence of oxaliplatin or CPT-11 pretreatment. RESULTS: Synergistic cytotoxicity was displayed when IC(30) of oxaliplatin or CPT-11 was combined with IC(10) and IC(30) of the fluoropyrimidines. One fluoropyrimidine did not achieve superior cytotoxicity over the others. After pretreatment with oxaliplatin or CPT-11, cytotoxic antagonism was observed as the concentration of a fluoropyrimidine increased up to IC(70). The increasing cytotoxic antagonism correlated with decreases in fluoropyrimidine nucleic acid incorporation. The most significant incorporation difference existed within the 5-FU treated group. CONCLUSIONS: No single fluoropyrimidine is more cytotoxically effective over the others when combined with oxaliplatin or CPT-11. Correlation of cytotoxic antagonism to the inhibition of fluoropyrimidine nucleic acid incorporation implies difficulties in drug transport and/or metabolism only after oxaliplatin or CPT-11 pretreatment.

Recombinant leukocyte interferon, doxorubicin, and 5FUDR in patients with hepatocellular carcinoma-A phase II trial.

PURPOSE: To study the combination of 5FUDR, recombinant leukocyte interferon (IFN), and doxorubicin in patients with unresectable hepatocellular carcinoma. METHODS: IFN was administered at a dose of 6 miu/m(2) subcutaneously followed in 2 h by doxorubicin 20 mg/m(2) intravenously. After doxorubicin, 5FUDR was given as a 24-h infusion at a starting dose of 80 mg/kg. The dose of IFN was escalated to three times a week if tolerated. Both doxorubicin and 5FUDR were administered once weekly. RESULTS: There were 30 patients entered into the study. Among the 30 patients, there were two partial responses (7%) and one patient had stable disease. Toxicity was generally tolerable with fever, and chills, fatigue, and myelosuppression as the most common side effects. CONCLUSIONS: This chemotherapy combination was generally well tolerated, but has limited activity in unresectable, advanced hepatocellular carcinoma.

Cytotoxic effects and mechanisms of an alteration in the dose and duration of 5-fluorouracil.

5-Fluorouracil (5-FU) is the most routinely administered drug in the treatment of colon cancer. The main mechanism of the drug is not completely understood and its method of administration has been strongly disputed. A 24-hour infusion of 5-FU has clinically yielded better response rates and lower toxicities in comparison to bolus administration, but an exploration into possible mechanisms needs to be performed. Experiments were conducted with two 5-FU resistant cell lines where cytotoxicity, thymidylate synthase (T.S.) activity, thymidine kinase (T.K.) activity, DNA and RNA incorporation, and T.S. expression were contrasted between a 10 microM/24 hour administration of 5-FU (simulating continuous exposure) and a 100 microM/1 hour schedule (simulating bolus administration). After 6 days from the initial exposure, the 10 microM/24 hour schedule (schedule A) inhibited more cell growth than the 100 microM/1 hour regimen (schedule B) by more than 38% and 17% in the two cell lines. After the 6-day observation, schedule A inhibited twice as much T.S. activity as schedule B. Incorporation of [14C]-5-FU into DNA and total RNA was higher in cells exposed to schedule A in comparison to schedule B over the 6 days. T.S. expression and T.K. activity patterns were variable over time. Thus, the exposure of 10 microM/24 hour 5-FU results in superior cytotoxicity when compared to a 100 microM/1 hour regimen and its effectiveness may be explained mechanistically by T.S. activity and DNA and RNA incorporation.

In the war against solid tumors arsenic trioxide needs partners.

In the past decade, the therapeutic potential of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL) was recognized. This encouraged other investigators to test the efficacy of ATO in the management of other hematological and solid tumor malignancies. Notably, as a single agent, arsenic trioxide did not benefit patients diagnosed with solid tumors. However, when it was combined with other agents, treatment benefit emerged. In this article, we have summarized the outcome of clinical trials that used arsenic trioxide as a single agent as well as in combination settings in patients diagnosed with solid tumors. We have also reviewed possible additional mechanisms by which ATO may be useful as a chemosensitizer in combination therapy. We hope that our review will encourage clinical investigators to rationally combine ATO with additional chemotherapeutic agents in treating patients diagnosed with solid tumors.

In Vitro Global Gene Expression Analyses Support the Ethnopharmacological Use of Achyranthes aspera.

Achyranthes aspera (family Amaranthaceae) is known for its anticancer properties. We have systematically validated the in vitro and in vivo anticancer properties of this plant. However, we do not know its mode of action. Global gene expression analyses may help decipher its mode of action. In the absence of identified active molecules, we believe this is the best approach to discover the mode of action of natural products with known medicinal properties. We exposed human pancreatic cancer cell line MiaPaCa-2 (CRL-1420) to 34 µ g/mL of LE for 24, 48, and 72 hours. Gene expression analyses were performed using whole human genome microarrays (Agilent Technologies, USA). In our analyses, 82 (54/28) genes passed the quality control parameter, set at FDR ≤ 0.01 and FC of ≥±2. LE predominantly affected pathways of immune response, metabolism, development, gene expression regulation, cell adhesion, cystic fibrosis transmembrane conductance regulation (CFTR), and chemotaxis (MetaCore tool (Thomson Reuters, NY)). Disease biomarker enrichment analysis identified LE regulated genes involved in Vasculitis-inflammation of blood vessels. Arthritis and pancreatitis are two of many etiologies for vasculitis. The outcome of disease network analysis supports the medicinal use of A. aspera, viz, to stop bleeding, as a cure for pancreatic cancer, as an antiarthritic medication, and so forth.